The applicant's long-term goal is to understand the role that an abnormal or inadequate innate immune response to viral infections may play in the initiation and pathogenesis of pediatric rheumatological diseases. Natural killer (NK) cells are cytotoxic lymphocytes that play a central role in the innate immune response to viral infections. They are particularly important in mediating resistance to large DNA viruses such as herpesviruses. This has been clearly demonstrated by recent work identifying the specific murine NK cell activation receptor and its virally encoded ligand responsible for resistance of mice to the herpesvirus, murine cytomegalovirus. Resistance to another family of large DNA viruses, the poxviruses, also appears to be mediated by NK cells. This proposal focuses on using the poxvirus, vaccinia, as a model for studying the in vivo responses of the innate immune system and specifically NK cells to poxvirus infections. Preliminary work performed by the applicant with his mentor, Wayne Yokoyama, suggests that NK cells are involved in conferring resistance to vaccinia infection in mice. The specific aims of this proposal are: 1) to characterize the cytokines involved in vaccinia-induced NK cell activation and proliferation, 2) to identify the murine NK cell activation receptor involved in mediating resistance to vaccinia, and 3) to evaluate the role of this receptor in providing in vivo resistance to vaccinia. The applicant is a physician with a Ph.D. in Chemical Engineering who is completing his fellowship training in Pediatric Rheumatology/lmmunology at Washington University School of Medicine. The work in this proposal is part of five-year career development plan to facilitate the applicant's transition to a career as an independent researcher. The proposed work will occur under the mentorship of Dr. Wayne Yokoyama a recognized pioneer in the NK cell field who has successfully trained numerous graduate students and postdoctoral fellows. [unreadable] [unreadable]